Since the year 2000 alone, more than 1,000,000 vascular prosthetic devices have been implanted worldwide. From stents to artificial heart valves and ventricular assist devices, a wide range of devices are being used to treat patients often expected to live for many years after the procedures. Since biomaterials promote surface-induced thrombotic phenomena to some extent, an ever-increasing pool of patients reliant upon indefinite anticoagulant therapy has been created. This is unfortunate, as the use of drugs like heparin, warfarin and clopidogrel carries a serious risk of side effects like bleeding, bruising and serious internal hemorrhage.
The study of thrombogenetic sequence originates at platelet response to endothelium damage. Although platelets can be activated in suspension, they are by nature adhesive elements which perform their hemostatic function under flow conditions. Whereas platelets will not interact with the endothelial layer that covers the vascular tree, they will rapidly respond to a mechanically damaged vessel. Within several minutes after injury, the exposed surface will be covered by a continuous layer of platelets.
The sequence of events developing after the endothelium becomes damaged is well established. Studies with blood circulating through vascular segments mounted in specially designed chambers have clearly established that initial platelet attachment is mediated through the interaction of insoluble von Willebrand factor (VWF) bound to subendothelium with the platelet glycoprotein Ib-IX complex (GPIb-IX). Additional interactions of platelet GPIIb-IIIa (known also as integrin α2bβ3) with the amino acid sequence Arg-Gly-Asp-Ser (RGDS) present on several adhesive proteins (fibrinogen, VWF and fibronectin) will play a major role on platelet spreading and aggregate formation.
All major receptors on the platelet membrane are connected via GTP regulatory proteins to cytoplasmic second-messenger-generating enzymes. Coupling of receptors with their specific agonist will generate a second messenger that raises the free calcium level in platelet cytoplasm. Increased levels of Ca++ will result in the amplification of activation mechanisms with cytoskeletal assembly, internal contraction, fusion and release of the alpha granules and expression of activation dependent antigens (CD-62P) that would facilitate crosstalk interactions with leukocytes. During this process of activation anionic phospholipids will become externalized at the membranes of activated platelets. These phospholipids will further facilitate mechanism of blood coagulation.
Blood contacting biomaterial surfaces in particular, have been shown to adsorb a layer of proteins from blood and to attract platelets. Build-up of blood components on the surface of implanted devices may reduce their effectiveness, and in many cases will lead to serious adverse complications or operational failure. Thrombogenesis presents a major problem associated with the clinical use of all kinds of prosthetics, and the prevention of unwanted clotting without the side effects incurred through the use of blood thinning drugs would be a major advancement in the field of biomaterials.
One method for securing biomaterials against unwanted thrombosis is to modify the biomaterial surface itself. For example, anti-thrombogenic materials have been covalently bonded onto the blood-contacting biomaterial surfaces. Additionally, the biomaterial has been treated to give its surface a fixed charge which can affect the biocompatibility of the material. In other cases, the surface has been polished to an extremely high degree. None of these techniques, however, have been completely effective in deterring platelet adhesion to the biomaterial surface.
Platelets will avidly interact with any foreign surface including any kind of artificial material. Mechanisms responsible for the interaction of platelets with artificial surfaces are mediated by the same glycoproteins described above, though functions of these glycoproteins are not identical to those described in the previous section. It is fully accepted that the presence of proteins adsorbed on the artificial surface play a crucial role in mediating the initial interactions of platelets with the surface, and the composition of the synthetic surface is a key determinant on the rate and nature of the protein adsorbed. Vroman and Cols demonstrated the effect named as “Vroman effect”, describing that a first protein was deposited on the surface after the initial contact of blood with a polymer surfaces, that initial protein was sequentially replaced by another protein. The nature of the adsorbed proteins has a critical influence on further platelet deposition. Albumin is known to inhibit platelet deposition on artificial surfaces in vitro. Contrarily to albumin, fibrinogen, fibronectin and von Willebrand factor enhance platelet interactions with the artificial surface. Two regions of the fibrinogen alpha chain that contain an RGD motif, as well as the carboxyl-terminus of the fibrinogen gamma chain, represent potential binding sites for GPIIb-IIIa in the fibrinogen molecule.
In essence, while the initial attachment of platelets with vascular subendothelium is initiated through interactions of GPIb-IX with vWF bound to collagen, the interaction of platelets with artificial surfaces may be considered to be mainly driven by GPIIb-IIIa and fibrinogen adsorbed onto the surfaces.
It has been theorized that promoting adhesion of albumin to the detriment of fibrinogen at the blood-contacting surface could be effective in altering the thrombogenicity of various materials. In fact, Grunkemeier et al., Biomaterials, November, 2000 pp. 2243-2252, and Tsai et al., Journal of Biomedical Materials Research Dec. 15, 2003, pp. 1255-68, found that the amount of adsorbed fibrinogen was the chief determinant of the degree of platelet adhesion, although platelets were most attracted to a surface when a combination of proteins was residing on the surface, including Von Willebrand factor. No preadsorption of particular blood proteins has yet been shown to prevent clotting entirely. It is very difficult to prevent fibrinogen from adhering to the biomaterial surface, and only a small amount of adhered fibrinogen is necessary to start a chain reaction leading to thrombosis.
Some materials coated with anticoagulant agents such as heparin have had limited success in preventing thrombosis. However, heparin coatings will eventually dissolve over time. Drawbacks to agent-eluting surfaces have also been realized. A study by Pfisterer et al., Journal of American College of Cardiologists, Dec. 19, 2006 pp. 2592-5 regarding the Basel Stent Kosten Effektivitats Trial, Late Thrombotic Events, suggested that between 7 and 18 months after implantation, the rates of nonfatal myocardial infarction, death from cardiac causes, and angiographically documented stent thrombosis were higher with drug-eluting stents than with bare metal stents.
Overall, there have been no recognized clinical advancements that could warrant replacing traditional anticoagulation therapy. At this time, only consistent maintenance of a regimen of blood thinning agents is clinically proven to prevent the dangerous thrombotic events associated with implants.
It is an object of the present invention to provide a system for conditioning a biomaterial surface to provide an anti-thrombogenic characteristic thereto.
It is another object of the present invention to provide a method for establishing an anti-thrombogenic characteristic to biomaterial surfaces, including surfaces of an implantable medical device.
It is a further object of the present invention to provide a packaging and delivery system for an implantable medical device.